The PSA debacle

So now it’s official.  The PSA screening test leads to a cascade of more tests and drastic treatments that cause serious harm AND saves no lives.  But there were plenty of warning signs 20 years ago, when the PSA test began to be aggressively promoted to men and their physicians. The demand for PSA screening was created by the companies that make the test, the equipment to diagnose prostate cancer, and the drugs to treat it. These companies also fueled consumer advocacy—but only the groups of cancer survivors who encouraged other men to undergo PSA testing. Now a panel of independent experts has announced its recommendation against PSA screening for healthy men at any age. In the meantime, a multibillion-dollar industry has grown up around PSA screening that’s not likely to disappear any time soon.

I became interested in the selling of prostate cancer screening somewhere around 1989, when prostate cancer went from obscurity to a widely feared disease.  It didn’t generate much interest because the average age at diagnosis was 75.  Autopsy studies of men who died of causes unrelated to cancer had already shown that the incidence of prostate cancer increases with age, 30% of men in their forties have prostate cancer, and by the time they reach their eighties, 70% have it.  Yet only 3% died of prostate cancer. The deaths were due to an aggressive form of prostate cancer, but it was not clear whether whether early detection and prompt treatment would make a difference. To this day, no test can accurately distinguish the aggressive form of prostate cancer from the type that’s slow-growing and not life-threatening.

What set prostate cancer apart from other cancers was the uncertainty about whether no treatment was superior to the drastic treatments like radical prostatectomy.  All this could be found in the 1989 version of cancer information from the database of the U.S. National Cancer Institute.  Of course, the NCI never put it that way.  Instead, “watchful waiting” (aka no treatment) was listed along with treatment options.  Severe treatment complications like impotence and incontinence were mentioned in the doctors’ version of this database, but not in the patients’ version. (Today, this database can be accessed directly at http://www.cancer.gov)

Screening creates customers, but first the public must be made to fear the disease and believe it can be treated successfully if found early. (Note how often your local hospital offers free cancer screenings.) Next, there must be easy access to the screening test. There was a time—around 1990—-when Merck thought its new drug Proscar had the potential for prostate cancer prevention. (It didn’t.) What was memorable about Merck’s early “prostate awareness” ads was the fact that some were aimed at women. They had a “get your man to the doctor” theme with no mention of Proscar, making them appear like public service announcements. Just one of many ways that set the path to a PSA.

By 1993 Gina Kolata would report in The New York Times that an astounding 92% of all American men had had a PSA screening test.  How did this test with no data to show it improves outcomes and a high rate of false alarms become so widely and quickly accepted by physicians and patients, she asked rhetorically.  Answer:  The demand had been created by the drug and device companies who sponsored the annual “Prostate Awareness Week”. (For the women’s version of this story read, “The Marketing of Osteoporosis”.)

In time, the PSA test would be included in the routine blood test with the result that men could now be given the test without their knowledge. Studies would show that most of the men who chose “watchful waiting” after a prostate cancer diagnosis could not live with the idea that they were living with an untreated cancer. The majority would go on to be treated.

In 2009 the results of two large clinical trials were published in the same issue of the New England Journal of Medicine.  Both compared men randomly assigned to receive either regular PSA screening test s or no screening. The results were devastating in terms of exposing  the high incidence of severe complications suffered by the men treated for prostate cancer as a result of PSA testing.  Only one study found screening reduced the rate of prostate cancer deaths, and it was minimal. The bad news about the PSA received plenty of media attention complete with quotes from urologists challenging the findings. click here

These two trials form the basis of the “new” recommendation against PSA screening by a 16-member panel of independent experts, sponsored by the U.S. Preventive Services Task Force.  This recommendation was actually decided back in 2009 after an in-depth review of all PSA-related studies, but not made public—that is, until October 7.  The New York Times (Sunday) magazine was about to print a hard-hitting article about PSA screening that would reveal that the task force recommendation had been withheld for nearly two years. Worse, the delay was due to fears that this unpopular conclusion would jeopardize the task force’s funding.

The predictable backlash came immediately—from doctor groups, especially the urologists, patient groups whose members believe their lives were saved by the PSA, and politicians against healthcare reform quick to charge “rationing”. In 2009, this charge was leveled at another task force that raised questions about the value of starting screening mammograms at age 40.

PSA screening has been called “the largest iatrogenic public health disaster of our time”.  It’s not over until men make it clear to their doctors that they do not want this test and make sure that it is not included in a routine blood test.

Maryann Napoli, Center for Medical Consumers©

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Anemia drugs hasten death in some cancer patients

For seven years Johnson & Johnson ran deceptive ads on prime time TV and in magazines with this recurring theme: A cancer patient cannot continue working because of debilitating fatigue due to chemotherapy. The ads told people in similar circumstances to ask their doctors about Procrit, which always quickly put an end to the fatigue. There is no published evidence to support the cure-for-fatigue claim, according to a 2007 press briefing at the FDA. Eventually, the agency required warning labels for Procrit, Aranesp, and Epogen —- all drugs widely prescribed to treat anemia in cancer patients. Warning label refers to the black box warning that appears in the 20 or so pages of information that comes with the drug (sometimes). The warnings for Procrit, Aranesp, and Epogen now list a higher incidence of potentially fatal blood clots, heart damage and increased tumor growth.

Now they can add “decreased survival” to the list. This week, the Cochrane Collaboration, the independent, international organization that evaluates research, published a meta-analysis of the information generated by the care of nearly 14,000 cancer patients entitled, “Anti-anemia drugs shorten survival for some cancer patients.” This meta-analysis is co-authored by Maryann Napoli, Center for Medical Consumers. For background on how their drugs came on the market and how financial incentives encouraged oncologists to overprescribe them, see her testimony on this topic before the FDA’s Oncologic Drug Advisory Committee in 2007 and one year later in 2008.

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The Marketing of Osteoporosis

How a risk factor (bone loss) became a disease (osteoporosis) by Maryann Napoli. Originally published in American Journal of Nursing, May 2009

Nurses probably get the same question I often get as a consumer advocate.  Should I be on this drug? You’re asked because you’re seen as the expert or simply a knowledgeable friend.  In fact, it’s a valid question not only to ask but also to look beyond the prescribing health care provider for answers.

In the name of prevention, millions of Americans have accepted the idea that it is reasonable to treat a risk factor (e.g., high cholesterol, bone loss) as if it were a disease. Think back to the 1990s when virtually all menopausal women were advised—pressured, according to accounts that came my way—by their gynecologists to go on hormone therapy to prevent heart disease and hip fractures.

More people should question the wisdom of going on long-term drug therapy. Often the magnitude of the risk factor has been overestimated; or the danger of the disease itself may be exaggerated by people trying to sell us something—like a drug you must take for the rest of your life.

Osteoporosis provides an excellent example of how the pharmaceutical industry begins creating a market for a new prevention drug years before it is approved.  The disease has become a major health concern for older women, though it was unknown to the general public until the early 1980s when the drug industry-led awareness campaign began.  It used to be that osteoporosis was not diagnosed until a fragility fracture had occurred.[1]

But a new definition, one based on bone mineral density, was established in 1993 at a World Health Organization meeting of osteoporosis researchers.  Its ostensible purpose was to determine the global prevalence of osteoporosis, but this meeting is where the definition of osteoporosis was radically changed.  What had been simply a risk factor (bone loss) became a disease (osteoporosis), complete with an arbitrary cutoff (bone density more than 2.5 standard deviations below the normal bone mass in young women).[2]

Overnight, the market for bone drugs had been expanded. Years after that WHO meeting, I would learn that it was sponsored by several pharmaceutical companies.² Hormone drugs were the standard preventive treatment at the time of the meeting, but three years later the first non-hormonal drug for bone loss—alendronate (Fosamax)—was launched.

Getting symptom-free women to accept drug therapy requires scarey statistics that imply the danger period starts right after menopause, leaving the impression that hip fractures, the most disabling consequence of osteoporosis, often occur soon after the hot flashes are over.  Here’s one stat you would see often: 24% women, aged 50 and over, die within a year of a hip fracture.[3]  And here’s one you don’t see often: over 90% of the hip fractures occur in people over 70 and the average age is 80.[4]  Elderly men have hip fractures, too, but the early marketing of alendronate was all about the ladies.

How Predictive are Bone Scans?

In the initial phase of the industry-funded osteoporosis awareness campaign, the scan known by the acronym DEXA was advised for women at the time of menopause. Scanning caught on in a big way, especially after Merck, the maker of alendronate, began financing the installation of DEXA machines in doctors’ offices.[5]  Nothing creates drug customers faster than getting people to be routinely scanned.

Unfortunately, scanning is not good at predicting which women in their early 50s will have a hip fracture at age 80. This was known in 1997 thanks to a report from the British Columbia Office for Health Technology Assessment, which—to my knowledge—is the first to reveal industry sponsorship of that 1993 WHO meeting where osteoporosis was redefined.[6]

Unfortunately, the report had no effect on U.S.testing guidelines, but consumer advocate Barbara Mintzes, Universityof British Columbia, summed up the situation nicely, “Bone mineral density testing is a poor predictor of future fractures, but an excellent predictor of start of drug use.”[7] Merck’s ads aimed at women did not even mention alendronate, they simply said, “Ask your doctor whether a bone density test is right for you.”  Sure, low calcium/vitamin D intake, scatter rugs, poor muscle strength, certain medications, impaired vision were given lip service as contributing factors to osteoporotic fractures, but loss of bone density always seemed front and center.

How Good is the Drug?

In the initial phase of DEXA promotion, many women in early middle-age, with low bone density but no history of fracture, were put on alendronate, despite the fact that the drug was tested only in elderly women with vertebral fractures. The results, even for this supposedly high-risk elderly group, were not impressive. In the Merck-sponsored three-year trial that received Food and Drug Administration approval, hip fractures occurred in 1% of those on alendronate, compared with 2% of those on a placebo. [8] (A “50% reduction in hip fracture” is the accurate, though misleading, way these results were often portrayed.)

Here is where the nurse/advocate can serve as a sounding board for patients deciding whether to go on drug therapy, helping them consider questions like:  Are you similar in age and fracture history to the women in this trial? What does that 1% fewer hip fractures mean to you? Let’s compare that 1% benefit with the 1.5% risk for a alendronate-induced esophageal ulcer found in this trial? Consider what happened to the study participants who did not take alendronate (98% of the untreated women—i.e., the placebo group—did not have a hip fracture).  The “script” for this discussion is the drug’s official FDA-approved label and the Physicians’ Desk Reference where the trials that won FDA approval are described.

When alendronate was put to the test for elderly women with bone loss but no vertebral fractures, the four-year trial showed that the hip fracture rate was no different for the drug-treated participants than it was for the women taking a placebo.In short, the drug is good at improving bone density but not so good at reducing hip fractures. This did not stop other drug companies from introducing their own alendronate knockoffs—risedronate, ibandronate, pamidronate, etidronate and zoledronic acid.  All are in the same drug class called bisphosphonates.  In an example of how long a drug has to be on the market before the full picture of harm is known, the FDA reported early this year that all bisphosphonates carry the risk of severe and sometimes incapacitating musculoskeletal pain.[9]

Drug Ad Campaign Misled Doctors

Why younger rather than elderly women became the likely recipients of a bisphosphonate prescription is no mystery.  Merck’s initial ads aimed at physicians encouraged it.  A multi-page glossy ad campaign that ran frequently in Annals of Internal Medicine featured a thin fortysomething white woman with a crumbling ancient stone column in the background.  “Don’t wait for a fracture… No matter what her degree of osteoporotic bone loss…” [10]  I wrote to the editor-in-chief of Annals, pointing out that alendronate had no proven benefit for women in early middle age.  Never got a reply, but Annals stopped running the ad about six months later.  Still, the message had already gone out, there and elsewhere—early middle age is the appropriate time to start fracture prevention with alendronate.  From the drug industry’s point of view, the younger customer is far more desirable than, say, the  elderly nursing home resident with a limited remaining lifespan in which to take drugs.

Today, women in the osteoporosis drug ads are usually in their early sixties.  The guidelines for bone density measurement currently recommend bone mineral testing not begin before age 65 (or 60 in some high-risk cases)[11], but now there’s a bigger problem.   Researchers have known, at least since 2000, that bone strength or bone quality are better predictors of hip fracture than bone density.  In 2001, the National Institutes of Health redefined osteoporosis as a combination of bone mineral density and bone quality. But there is no test for bone  quality or bone strength. ¹

It’s going to take time for the word to get out.

How relevant is this story to other drugs people take to treat a risk factor?  In a word: very.  Three-fourths of all Americans on cholesterol-lowering statins, the country’s top-selling drugs, do not have heart disease and are thus far less likely to benefit than people who do. [12]  (Statins are terrific at lowering cholesterol, but much less impressive at reducing the risk for heart attack[13]—sound familiar?)  The thresholds for high cholesterol[14] and high blood pressure were lowered several times over the years, each time making millions more people eligible for drug therapy. ⁵ 

Drug ads and industry-sponsored “education” programs are no longer the only major sources of biased information. Industry funding compromises the directives of non-profits like the American Heart Association and the American Cancer Society, as well as the experts who write treatment guidelines. [15]  One example of the latter: eight of the nine doctors who served on the 2004 government committee that expanded the guidelines for cholesterol-lowering drug therapy had financial ties to statin companies.[16]

More than ever, nurses must be knowledgeable advocates for their patients. You may be the last of the independent health professionals.

For More Information:

Added May 19, 2012: New take on bone density retesting.  and  Warning on bone drugs:  Stop after 5 years.

http://courses.washington.edu.bonephys    Web site of bone physiologist and osteoporosis researcher Susan Ott, MD, Associate Professor, Department of
Medicine, University of Washington.  Mostinteresting section: “When [drug] studies don’t give clear answers.”  Definitely take the quiz. (Accessed June 12, 2008.)

 

---

[1] Cheung, AM and Detsky, AS. “Osteoporosis and Fractures: Missing the
Bridge?” JAMA. 2008;299(12):1468-1470.

2 Kazanjian A, et al. Normal bone mass, aging
bodies, marketing of fear: bone mineral density screening of well women. University of British Columbia Centre for Health
Services and Policy Research. British Columbia Office of Health Technology Assessment BCOHTA  98:10C Sept 1998. http://www.chspr.ubc.ca/files/publications/1998/bco98-10C.pdf  (AccessedJune 13, 2008.)

[3]
National Osteoporosis Foundation. www.nof.org
(Accessed June 5,
2008)

[4]
Love S.M. with Lindsey, K.  Dr. Susan
Love’s Menopause & Hormone Book.  New York: Three Rivers
Press, 2003.  P.109

[5]
Moynihan R and Cassels A. Selling
Sickness: How the world’s biggest pharmaceutical companies are turning us all
into patients. New York: Nation Books, 2005 page 142.

[6]  Kazanjian A, et al.  Bone Mineral Density Testing: Does the
Evidence Support Its Selective Use in Well Women? 1997 British Columbia Office for Health Technology
Assessment, University of British Columbia.  http://www.chspr.ubc.ca/files/publications/1998/bco98-07C.pdf   (AccessedJune 5, 2008)

[7] Mintzes, B. Direct to consumer advertising is medicalising normal human experience. BMJ 2002;324:908-911.

[8]Physicians’ Desk Reference, 59^th edition 2005, page 2051.

[9] FDA Alert: Bisphosphonates (marketed as Actonel, Actonel+Ca, Aredia, Boniva, Didronel, Alendronate, Alendronate+D, Reclast,
Skelid, and Zometa). Posted Jan 7, 2008. http://www.fda.gov/medwAtch/safety/2008/safety08.htm#  (AccessedJune 12, 2008.)

[10] Napoli M. Alendronate: A new drug with an ad campaign that encourages misuse.   HealthFacts. July 1996.

[11] Agency for Healthcare Research and Quality. U.S. Preventive Services Task Force. Sept 2002. http://www.ahrq.gov/clinic/uspstf/uspsoste.htm
(Accessed June 13, 2008.)

[12]
Abramson J, et al. Are Lipid-Lowering Guidelines Evidence-Based? Lancet. 2007
Jan 20;369 (9557):168-9.

[13]
Carey J. Do cholesterol drugs do any good? Business Week, Jan 17,2008.
(Accessed onlineJune 16, 2008.)

[14]
Center for Science in the Public Interest. http://www.cspinet.org/integrity/press/200409231.html
(Accessed June 6, 2008).

[15]
Lenzer
J. Education and debate:  Alteplase for
stroke: money and optimistic claims buttress the “brain attack”
campaign.  BMJ 2002;324:723-729.  http://bmj.bmjjournals.com/cgi/content/full/324/7339/723#B14
(Accessed June
13, 2008.)

[16] National Cholesterol Education Program. Third Report of the Panel on Detection, Evaluation, and Treatment of high blood cholesterol in adults (Adult treatment panel III) 2004. http://www.nhlbi.nih.gov/guidelines/cholesterol/atp3upd04_disclose.htm                    (Accessed June 6, 2008).

Our Daily Meds: A book review

Yes, we knew that the pharmaceutical industry has been creating new diseases for at least four decades (recall how menopause became a hormone-deficiency disease curable by taking estrogen for the rest of your life). But the author of Our Daily Meds, a new book by journalist Melody Petersen, shows that one drug company, Pharmacia, was not shy about acknowledging it publicly.

Overactive bladder was created by Pharmacia in the mid-1990s in order to sell its new drug Detrol. (See TV ads with this obnoxious voice-over: “Gotta go, gotta go, gotta go right now.”) Petersen, then a business reporter for The New York Times, describes how she covered the 2003 Pharmaceutical Marketing Global Summit in Philadelphia, where Neil Wolfe, Pharmacia’s vice president, outlined the steps taken to make Detrol into the $3 billion a-year-product it is today. The first slide of his presentation: “Positioning Detrol (Creating a Disease).”

Detrol was initially intended as a treatment for urinary incontinence, but the market for this condition was too small, and a cheap alternative drug was already available. Besides, doctors weren’t keen on prescribing drugs for what was seen as a normal part of aging. Pharmacia’s first step in overcoming these obstacles was to hire doctors judged to be knowledgeable opinion leaders (KOLs) as “consultants,” fly them to medical meetings, including two symposia in London, where they were expected to come to a consensus about the definition and treatment of this new disease called overactive bladder. While being expensively wined and dined, the doctors heard from other doctors hired by Pharmacia about the disabling consequences of having to go to the bathroom more than eight times in a 24-hour period. If any KOLs objected to such an absurd notion, no such comments made it into the dozens of articles that Pharmacia paid to have written for medical and lay publications about the benefits of Detrol, writes Peterson. “And another disease was born.”

After a new disease is identified, the next step is creating buzz in the media. Of course, there’s no story unless the disease is perceived as extremely prevalent. No problem, the necessary statistics are generated by Pharmacia-financed surveys and passed on by a credulous media, including publications that should know better. (Consumer Reports lists Detrol as one of its “Best Medicines for Less 2008” along with this statistic: “overactive bladder affects some 15 to 20 million people in the U.S.”)

The standard formula for disease creation is complete once the drug maker saturates the airways, print media and medical journals with ads for Detrol. (Pfizer took over this role when it bought Pharmacia in 2002.)

Fast forward to the fall-out now that Detrol has been on the market for nearly a decade. New adverse effects have come to light—hallucinations and memory impairment, severe enough to be mistaken for Alzheimer’s disease. Oh, and there’s that question hardly anyone seems to ask (and not addressed in this book): How good is Detrol at reducing the number of trips to the toilet? The 12-week trial that won FDA approval showed that people taking Detrol LA (long-acting) had one less “episode” a week than those taking a placebo. Detrol costs $4 to $6 a day, depending upon where it is purchased.

The story of Detrol is but one of many jaw-dropping nuggets of information from Our Daily Meds. Here are a few more:

-Prescription medicine is one of the leading causes of death in the U.S., estimated to kill 270 people a day.
-Americans spent $197 billion on prescription drugs in 2003—up from $12 billion in 1980.

-It can take a hundred years before all the risks of a medicine are known, said FDA’s Janet Woodcock, in a 2005 presentation to a panel of experts reviewing the safety of the nation’s drugs.

-Once, the most successful pharmaceutical companies were those with the brightest scientists searching for cures. Now the most profitable and powerful drugmakers are those with the most creative and aggressive marketers.

-The pharmaceutical industry spent more on lobbying between 1998 and 2004 than any other industry. It has won new laws that have allowed the companies to profit from medical discoveries made by taxpayer-funded scientists. And when these new measures boosted the drug companies’ profits, other laws gave them tax credits so lucrative that as a group they pay far lower taxes on average than other major industries.

-The public is told that high profits are needed due to the high cost of innovation, but in fact the true cost of developing a new medicine is actually a closely guarded secret. What’s more, the industry hasn’t come up with many innovative drugs in the last 20 or so years.

-“Copycat drugs” are the money-makers. It’s much easier to cash in on a competitor’s blockbuster with a “new” drug that is virtually the same, simply by making doctors and consumers think it is better or has fewer annoying side effects.

The most troubling aspect of the industry’s marketing practices is the extent to which they have corrupted medical research. Over the course of the last 25 years, drug companies have been using clinical trials and medical journals to market their products. This trend was described as “the marketing approach to research” by Richard Daly, senior VP , Takeda Pharmaceuticals, at a 2002 breakfast meeting in Manhattan of executives from the largest pharmaceutical companies and advertising companies that work with them. The marketers aren’t working with test tubes and injecting patients, Petersen explained, “Instead they are standing besides the scientists, telling them what studies to do, what research questions to ask, what data to gather.”

Withholding data about serious adverse reactions from drug trials has become so common that there’s a medical term for it—“selective reporting” of trial results, also known as cherry-picking only the results the drug company wants made public. No one knows how many pharmaceutical studies have been kept secret after they showed a drug does not work or caused harms, writes Petersen, but several reviews have found that at least 50% of pharmaceutical trials were never published. Thus, a complete picture of a drug’s harms is unknown.

Prescribing physicians can no longer trust the information published in medical journals. And the doctor-patient relationship itself has become severely compromised by drug marketing. It is nearly impossible for most people to know whether their doctors are prescribing on the basis of the best available scientific evidence or the best available marketing scheme.

Petersen put it this way: “The pharmaceutical companies have become so wealthy and powerful that the whole medical system has become unbalanced. Inside hospitals and medical offices, corporate marketers are now calling the shots. They decide how patients will be treated and the doctors follow along. How else can you describe a system where doctors now prescribe a pill called Detrol for a disease called overactive bladder.”

Reviewed by Maryann Napoli, Center for Medical Consumers© August 2008

Women-in-Towels Evista Ad Critiqued

The women in Eli Lilly’s new ad campaign are attractive, healthy-looking and wearing nothing but towels. “Cut two risks with Evista. The only agent indicated to treat osteoporosis and reduce the risk for invasive breast cancer.”

That two-for-one claim for Evista makes it different from other drugs taken by symptom-free people. Studies showed that the harm related to each disease drops a percentage point or two in those who took Evista, compared to those who did not. The drug is better than a placebo (or it would not get FDA approval), but not much better. This is a recurring theme in Center for Medical Consumers articles because it’s a recurring theme in many drug trials. And often the small risk of a serious adverse reaction to the drug equals that small chance of benefit.

Evista (generic name: raloxifene) has been on the market since 1997 as an osteoporosis drug. It produces a 2%-3% increase in bone density; reduces the rate of vertebral (spinal) fractures; but does not prevent the most serious type of fracture (hip). Vertebral fractures can cause pain and a dowager’s hump in advanced age, but many are symptomless. The studies did not last long enough for Lilly to make claims regarding prevention of a dowager’s hump or loss of height.
Breast Cancer “Risk Reduction”

Last year Lilly received FDA approval to promote Evista as a drug that can “reduce the risk of invasive breast cancer.” This careful wording from the Evista ads is important. Lilly cannot claim its drug prevents breast cancer because the disease can take anywhere from 8 to 17 years to develop. There were, in fact, fewer breast cancers diagnosed in the women taking Evista, compared to those taking placebos. But the trials didn’t last long enough to determine whether the drug prevents breast cancer or simply delays its onset. In Evista trials that lasted up to eight years—breast cancer was diagnosed in 2.5% of the women taking a placebo and 1% of the women taking Evista.

The other claim for Evista is based on the fact that the women in the studies already had osteoporosis (bone loss). One way bone drug companies can inflate the benefit of their product is to count symptomless vertebral fractures that can be detected only on x-ray. (In other words, the women are unaware of them.) At the start of the Evista trial about half the women had painful vertebral fractures and the other half had “fractures diagnosed radiographically.” After four years, things looked better for Lilly when results for all women were combined, but less impressive when women with painful fractures were singled out. In the latter group, only about 1% fewer Evista-treated women had new painful vertebral fractures than the women taking placebos.

Thus far serious adverse reactions to Evista include deep vein thrombosis, pulmonary embolism, retinol vein thrombosis and an increased risk of fatal stroke. (See boxed warning of the FDA-approved label). Separately, each is classified as rare, which, according to FDA standards, describes any drug reaction that occurs in less than 2% of study participants. Collectively, though, these potentially fatal adverse reactions could reach 1-2% which comes close to the percentage of women who benefited from Evista in the FDA-required clinical trials.

And lastly, the visual message conveyed by the women-in-towels ad is misleading. Most of the women look to be in their fifties. At the start of the Evista trials, however, most participants were over age 65 years, a time of life when vertebral fractures are far more likely to occur.

Maryann Napoli, Center for Medical Consumers ©
July 2008

Anemia Drugs For Cancer Patients

Testimony Submitted to FDA Oncologic Drugs Advisory Committee Meeting
March 13, 2008

Maryann Napoli, Associate Director, Center for Medical Consumers

As a consumer advocate who attended the May ODAC meeting, I came away wondering why these drugs remain on the market. They cause some patients to die sooner. They have many other risks that are severe and well documented, and any quality-of-life benefit has yet to be proven. The FDA approved the first ESA because it reduced the percentage of patients transfused. But the agency has since acknowledged that the infectious disease risks of a blood transfusion are far lower now than they were in 1993.

No doubt there are many cancer patients who see these drugs as an instant cure for chemotherapy-induced fatigue or as the means of allowing chemotherapy to continue. The former indication was fostered by Johnson & Johnson’s fraudulent ad campaign for Procrit, which continued for seven years in the mainstream TV and print media. I urge ODAC to discuss the misconceptions imparted by these ads and to consider recommending that the FDA require J&J to run a corrective ad campaign.

The ability of a cancer patient to make a truly informed decision with the help of her oncologist is seriously compromised by J&J’s and Amgen’s reprehensible practice of offering rebates—that is, kickbacks—to oncologists. Patients are always encouraged to discuss their treatment decisions with their doctors. Yet it’s hard for patients to believe oncologists’ recommendations are unbiased when they are “reaping millions” from the prescription of anemia drugs, as The N.Y. Times reported last May. (1) Companies that give kickbacks and other financial incentives intended to manipulate oncologists into using the most expensive drugs are poisoning the doctor/patient relationship.

Where can people turn for unbiased information? It should be the FDA, but it’s not clear to me that black box warnings are the way to go. The changes in the product labeling in 2004 did not change clinical practice. (2) And what do we know about the effects of black box warnings on the ones who need them the most—the cancer patients? The cancer patient should be given scientifically accurate, written information about ESA well before she needs it. The time to weigh the risks and benefits is not when she’s awaiting her next chemo treatment and just learned that her hemoglobin is too low for the next round.

Patients cannot make truly informed decisions unless they are given quantitative information to help them decide whether ESA is appropriate. They need to know, for example, the chances of…1) needing a transfusion; 2) suffering harm by foregoing a transfusion, 3) experiencing a serious adverse effect from the transfusion itself, and 4) having a severe adverse effect from the ESA. Patients need to know the magnitude of each of these four risks. Telling them that ESA will reduce their risk of having a blood transfusion is simply too vague. It gives them no way to compare this purported benefit with the other risks of taking ESA. If the FDA will not remove these drugs from the market, it must find the best ways to get clearly written, accurate quantitative ESA information to cancer patients.

(1) Berenson A, Pollack A. “Doctors Reap Millions for Anemia Drugs.” N.Y. Times, May 9, 2007

(2) Blau AC. “Erythropoietin in Cancer: Presumption of Innocence?” Stem Cells 2007; 25;2094-2097; originally published online Apr 26, 2007.

Honesty in Drug Advertising: Some rare examples

“In patients with multiple risk factors for heart disease, LIPITOR REDUCES RISK OF HEART ATTACK BY 36%* If you have risk factors such as family history, high blood pressure, age, low HDL (‘good’ cholesterol) or smoking.”

The noteworthy part of this New York Times ad is the asterisk and this explanation of the 36% statistic: “That means in a large clinical study, 3% of patients taking a sugar pill or placebo had a heart attack compared to 2% of patients taking Lipitor.”

Take a moment to appreciate the significance of this rare finding of candor in one of those ubiquitous Lipitor ads featuring Dr. Robert Jarvik, “inventor of the Jarvik Artificial Heart and Lipitor user.” Most drug ads would rather proclaim a “36% reduction” and leave it at that, but this version shows exactly what it means. Take Lipitor for years and your risk of having a heart attack drops 1%. Granted, the explanation is in much smaller type than the 36%, but at least it’s there.

Another Jarvik/Lipitor Times ad proclaims: “In patients with type 2 diabetes, LIPITOR REDUCES RISK OF STROKE BY 48%* If you also have at least one other risk factor for heart disease…” The explanation: “That means in a large clinical study, 2.8% of patients taking a sugar pill or placebo had a stroke compared to 1.5% of patients taking Lipitor.”

It’s rare to see ads with drug benefits expressed in what statisticians call absolute risk terms, which are more understandable to the public as well as doctors. Tom Abrams, director of the FDA Division of Drug Marketing, Advertising and Communications, explained in a telephone interview that the FDA encourages drug companies that provide quantitative information (e.g., 36% reduced risk of heart attack) in their ads to show what it means. In other words, the ad must answer the question: 36% of what?

Whether quantitative information goes into an ad is up to the drug companies, but once it does, the FDA wants them to put in the explanation, Abrams said, though only the most egregious non-compliers get a warning letter. Why no explanation of the quantitative information in all TV versions of these ads? “This is a quicker media and companies believe that people can’t process the information?” he said.

Well, honesty in some print ads is better than nothing. The next thing to look for is the quantification of the drug’s severe adverse effects…in absolute risk terms.

Maryann Napoli, Center for Medical Consumers ©
May 2007

Those Ubiquitous Gardasil Ads

The first thing you notice about the Gardasil TV ads, featuring teen-age girls engaged in various athletic activities, is that there is no mention of the fact that the Gardasil vaccine is for the prevention of a sexually transmitted disease.

The voiceover says, “Every year thousands of women die of cervical cancer. I want to be one less woman who will battle cancer.” The first sentence is entirely true (3,700 in the U.S.); the second is merely a wish.

One version of these ads, which features mothers and daughters, was found to be cleverly manipulative by a New York Times reporter, Claire Dederer. The ad shows cool, self-reliant girls involved in cool, self-reliant physical activities with the repeat message: I want to be one less woman who will battle cancer.

“The mothers appear about halfway through [the ad] and they’ve got the bad news,” writes Dederer. “In loving tones they break it to their daughters: ‘Gardasil may not fully protect everyone,’ they say. Tenderly they list the side effects.This is an ingenious ploy: the cool girls want to be ‘one less’; the moms are the ones putting on the brakes. Having mothers voice the downside of Gardasil reinforces the message that if you get this vaccination, you’re the rebellious, independent thinker: ‘forget the side effects. Forget Mom. I’m getting vaccinated.’”

Maryann Napoli, Center for Medical Consumers© March 2007

Dueling Osteoporosis Drug Ads

The goal of osteoporosis drug therapy is not to stop bone loss or improve bone density. Rather it is to reduce the chance of having a serious fracture. Over the years, osteoporosis researchers have found that improving bone density does not always lead to fracture reduction. The drug class called bisphosphonates has dominated the osteoporosis drug market ever since Fosamax became available in 1994. Actonel, another bisphosphonate soon followed. Boniva is the latest drug in this class.

How good are these drugs at reducing the rate of hip fracture, the most serious consequence of osteoporosis? Not very. The first clinical trial proving Fosamax’s benefit showed that at three years, 1% of the drug-treated women had had a hip fracture, compared with 2% of the women on the placebo. Significantly, the elderly women in this trial all had evidence of a previous fracture; whereas many younger women are inappropriately put on long-term Fosamax purely because a bone-mineral density test showed bone loss.

As Fosamax nears the end of its patent life, its competitors, Actonel and Boniva, are promoted in ads that emphasize the fact that they do not have to be taken daily. For example, the TV and print ads for Boniva feature its once-a-month dose convenience, but the ads for once-a-week Actonel also mention its proven fracture-prevention. These two different promotional approaches merit scrutiny.

What did the clinical trials prove?

In a three-year trial, Boniva was no better than a placebo in reducing non-spinal fractures (hence the Boniva ads’ focus on once-a-month dosing). As for Actonel, its advertised claims are correct but misleading: “Actonel is clinically proven to help protect many bones where a woman is most vulnerable to fractures caused by osteoporosis: The spine and a combination [emphasis added] of wrist, hip, collarbone, upper arm, leg and pelvis.”

Clustering the non-spinal fractures together clearly makes the clinical trial results look more impressive. 11% rate of the women on a placebo had a non-spinal fracture, compared to 7% for the women on Actonel.  However, where it concerns hip fracture, the same trials showed Actonel to be much less impressive. The rate of hip fracture of the women on Actonel was identical (2%) to that of the women on the placebo. (These findings appear in Actonel’s “label,” known as the packet insert which provides prescribing information for doctors.)

Who were the study participants?

In both the Boniva and the Actonel clinical trials, the participants were postmenopausal women with documented osteoporosis—that is, spinal fractures shown on x-ray—but only some had symptoms. In many cases, women are unaware of their spinal fractures.

Cautions

The bisphosphonates, particularly Fosamax and Actonel, are usually prescribed for five years or more. In her excellent Web site, Susan Ott, MD, one of the country’s leading osteoporosis researchers, explains why five years is enough. “The bisphosphonates get deposited in the bone and will accumulate for years. It is possible that many years of continuous medicine would make bone more brittle or impair the ability to repair damage. Bisphosphonates do reduce fractures and improve measurements of bone strength for the first five years in both animal studies and in women who have osteoporosis. After five years, the fracture rates are as high in the women who keep taking alendronate [Fosamax] as in the women who quit.” (http://courses.washington.edu/bonephys)

Alternatives:

Reduce the chances of falling by eliminating scatter rugs from the home and by avoiding certain prescription drugs like tranquilizers and barbiturates. Regular exercise will also reduce the risk of fracture.  Daily supplements of 1000 mg calcium and 800 IU vitamin D3 decrease the likelihood of a first hip fracture, according to an analysis of relevant clinical trials published last year in the Journal of the American Medical Association. This is a lower amount of calcium and a higher amount of vitamin D than the longstanding recommendations.

For updates on this topic, read our more recent articles: Prevent falls with vitamin D3, “The Marketing of Osteoporosis—How a risk factor became a disease,” (April 2009 issue of the American Journal of Nursing), “Fosamax-induced osteonecrosis of the jaw—more common than previously thought,” and “Osteoporosis drug: New adverse effects.”

Maryann Napoli, Center for Medical Consumers ©

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Painkiller’s Ads Hype New Combo of Old Drugs

Combunox:

Combunox is advertised by Forest Pharmaceuticals as though it were a new drug. Actually, it is a combination of two old drugs: the semi-synthetic opioid prescription drug, oxycodone, plus the popular over-the-counter anti-inflammatory painkiller, ibuprofen. The combination supposedly provides an extra punch. But The Medical Letter (1/2/06), a physician publication without drug advertising, assessed the studies supporting the use of this fixed combination drug and concluded that people with acute pain might be better off taking ibuprofen alone.

At a dose of 400 mg (the amount in Combunox), ibuprofen is doing the lion’s share of the painkilling. “A 400-mg dose of ibuprofen is generally superior to 1000 mg dose of acetaminophen (brand name: Tylenol) and is comparable to acetaminophen/codeine combinations,” according to The Medical Letter. “The analgesic effect of ibuprofen does not increase with doses greater than 400 mg; the anti-inflammatory effect does and so does the drug’s gastrointestinal toxicity.”

Who were the study participants?

In one clinical trial, Combunox was better than a placebo in women with moderate to severe pain 14 to 48 hours after abdominal or pelvic surgery, and in another trial that involved people who have had dental surgery.

What’s New About Combunox?

Not much. Oxycodone was introduced over 50 years ago and reintroduced in the ensuing years under numerous brand names (including OxyContin and Percolone) and in combination with over-the-counter painkillers, such as aspirin/oxycodone (Percodan) and acetaminophen/oxycodone (Percocet). Combunox represents the first time oxycodone has been combined with ibuprofen.

Cautions

Combunox is approved for the short-term (seven days) treatment for moderate to severe acute pain because prolonged use can lead to dependence. The warning is based on longstanding concerns about oxycodone. As with all opioids, abuse is a strong possibility. Under its most popular brand name OxyContin, oxycodone has received considerable media attention because of continuing reports of abuse. One risk of taking a fixed combination, according to The Medical Letter is this: Dependence upon oxycodone may cause people to increase the dose, which in turn could lead to overdosage of ibuprofen.

Alternatives

A week’s supply of Combunox costs $10.08 to $40.32, says The Medical Letter, whereas, the same amounts of generic ibuprofen and oxycodone would cost $4.80 to $19.20. The Medical Letter findings suggest that 400 mg of ibuprofen alone might be the safest choice.

Maryann Napoli, Center for Medical Consumers ©
February 2006